title: Microtubule Actin Cross-linking Factor 1 regulates cardiomyocyte microtubule distribution and adaptation to hemodynamic overload.
abstract: Aberrant cardiomyocyte microtubule growth is a feature of pressure overload induced cardiac hypertrophy believed to contribute to left ventricular (LV) dysfunction. Microtubule Actin Cross-linking Factor 1 (MACF1/Acf7) is a 600 kd spectraplakin that stabilizes and guides microtubule growth along actin filaments. MACF1 is expressed in the heart, but its impact on cardiac microtubules, and how this influences cardiac structure, function, and adaptation to hemodynamic overload is unknown. Here we used inducible cardiac-specific MACF1 knockout mice (MACF1 KO) to determine the impact of MACF1 on cardiac microtubules and adaptation to pressure overload (transverse aortic constriction (TAC).In adult mouse hearts, MACF1 expression was low under basal conditions, but increased significantly in response to TAC. While MACF1 KO had no observable effect on heart size or function under basal conditions, MACF1 KO exacerbated TAC induced LV hypertrophy, LV dilation and contractile dysfunction. Interestingly, subcellular fractionation of ventricular lysates revealed that MACF1 KO altered microtubule distribution in response to TAC, so that more tubulin was associated with the cell membrane fraction. Moreover, TAC induced microtubule redistribution into this cell membrane fraction in both WT and MACF1 KO mice correlated strikingly with the level of contractile dysfunction (r(2) = 0.786, p<.001). MACF1 disruption also resulted in reduction of membrane caveolin 3 levels, and increased levels of membrane PKCα and β1 integrin after TAC, suggesting MACF1 function is important for spatial regulation of several physiologically relevant signaling proteins during hypertrophy. Together, these data identify for the first time, a role for MACF1 in cardiomyocyte microtubule distribution and in adaptation to hemodynamic overload.
authors.affiliation: Cardiovascular Division and Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America.
authors.forename: John T
authors.initials: JT
authors.lastname: Fassett
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Dongmin
authors.initials: D
authors.lastname: Kwak
authors.forename: Huan
authors.initials: H
authors.lastname: Wang
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.forename: Xinli
authors.initials: X
authors.lastname: Hu
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bache
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D001483:Base Sequence; D051244:Caveolin 3 / Q000502:physiology; D017931:DNA Primers; D004452:Echocardiography; D006439:Hemodynamics; D019012:Integrin beta1 / Q000502:physiology; D008168:Lung / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000502:physiology*; D008870:Microtubules / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D051571:Protein Kinase C-alpha / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left
chemical_list: D051244:Caveolin 3; D017931:DNA Primers; D019012:Integrin beta1; C490632:Macf1 protein, mouse; D008840:Microfilament Proteins; D051571:Protein Kinase C-alpha